TWI731064B - Composition for Tie2 activation - Google Patents

Abstract

The subject of the present invention is to provide a composition having Tie2 activation effect, vascular permeability inhibitory effect, blood vessel maturation effect, blood vessel normalization effect, blood vessel stabilization effect, lymphatic vessel stabilization effect, etc.

The solution of the present invention is that the composition contains at least one component selected from the group consisting of novel iridoid glycoside compounds (Compound A, Compound B), oleanolic acid glycoside A, and kaempferol .

Description

Tie2 activation composition

The present invention relates to a composition for activation of Tie2 and the like. In more detail, the present invention relates to a compound selected from the group consisting of novel iridoid compounds (Compound A and Compound B), oleanoside A (Oleanoside A), and kaempferol (Kaempferol). Tie2 activation composition, vascular permeability inhibiting composition, blood vessel maturation composition, blood vessel normalization composition, blood vessel stabilization composition with one or more components in the group as active ingredients Composition, and composition for stabilizing lymphatic vessels. In addition, the present invention also relates to novel iridoid glycoside compounds (Compound A and Compound B) and compositions containing the compounds.

Olive (Olea europaea) is a plant belonging to the Oleaceae Oleaceae and began to be widely cultivated in the Mediterranean region. Its fruit is widely used as an extraction or food for olive oil all over the world.

In olive fruits, it is reported that polyphenols such as hydroxytyrosol, acteoside, oleuropein, etc. are abundant (Non-Patent Documents 1 and 2), olive extracts or their polyphenol components have arteriosclerosis Inhibition (Non-Patent Document 3), Hypertension Inhibition (Patent Document 1) Inhibition of bone weight loss (Non-Patent Document 4), etc.

In recent years, it has been discovered that the aging or decreased function of blood vessels can affect skin properties such as wrinkles or rough skin. It is known that the normality of blood vessels is an effective indicator for judging skin properties. This blood vessel not only transports oxygen or nutrients to the organs of the body through the blood, but also transports the excrement from the tissues to the external excretion. It is an important tissue for the human body to maintain life activities. Generally speaking, aging or functional failure of blood vessels, such as arteriosclerosis, has a significant impact on human health, and is also related to appearance results such as wrinkles or edema. In recent years, the activation of receptor-type tyrosine kinase with Ig and ECF homology domain 2 (Tyrosine kinase with Ig and ECF homology domain 2) is attracting attention for the aging of this blood vessel. It is known that when Tie2 is activated by angiogenin-1 derived from the wall cells of blood vessels, the adhesion between cells derived from vascular endothelium contributes to the stabilization of vascular endothelial cells. In recent years, it has been discovered that ingredients or foods with this Tie2 activation effect are used in supplements or beverages for the purpose of beauty, prevention of edema, prevention of sensitivity to cold, etc. (Patent Documents 2 to 4).

[Prior technical literature] 〔Patent Documents〕

[Patent Document 1] Japanese Patent Application Publication No. 2005-334022

[Patent Document 2] JP 2014-097977 A

[Patent Document 3] JP 2013-241356 A

[Patent Document 4] JP 2011-102272 A

〔Non-patent literature〕

[Non-Patent Document 1] J. Agric. Food Chem., vol.52, pp479- 484, 2004

[Non-Patent Document 2] J. Agric. Food Chem., vol.53, pp8963-8969, 2005,

[Non-Patent Document 3] Atherosclerosis, vol.188, No.1, pp35-42, 2006

[Non-Patent Document 4] Clin. Nutr., vol. 25, No. 5, 859-868, 2006

The subject of the present invention is to provide a composition with Tie2 activation effect, vascular permeability inhibitory effect, blood vessel maturation effect, blood vessel normalization effect, blood vessel stabilization effect, and lymphatic vessel stabilization effect, etc. .

In order to solve the above-mentioned problems, the inventors of the present inventors have conducted diligent studies and discovered that oleanolic acid A and kaempferol have Tie2 activation, vascular permeability inhibitory effects, and other components isolated from olive fruit extracts. The maturation effect of blood vessels, the normalization effect of blood vessels, the stabilization effect of blood vessels, and the stabilization effect of lymphatic vessels, etc. Furthermore, while discovering novel iridoid glycoside compounds (Compound A and Compound B) from the aforementioned olive fruit extract, it was also revealed that the novel compound has Tie2 activation, vascular permeability inhibition, vascular maturation, and vascular maturation. The normalization effect, the stabilization effect of blood vessels, and the stabilization effect of lymphatic vessels, etc., have finally completed the present invention.

That is, the aspects of the present invention are not limited to these, but include the following inventions.

(1) A composition for Tie2 activation, which contains a compound selected from the group consisting of the compound represented by (I) below, the compound represented by (II) below, the compound represented by (III) below (Oleanoside A), and the following ( IV) The compound represented (Kaempferol) and one or more components in the group formed by the salt:

(2) A composition for inhibiting vascular permeability, which contains a compound selected from the group consisting of the compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), and the compound represented by (IV). The compound (Kaempferol), and one or more components in the group formed by the salt.

(3) A composition for vascular maturation, which contains a compound selected from the group consisting of the compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), and the compound represented by (IV). The compound (Kaempferol), and the group of these salts One or more ingredients.

(4) A composition for normalizing blood vessels, which contains a compound selected from the group consisting of the compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), and the compound represented by (IV). The compound (Kaempferol), and one or more components in the group formed by the salt.

(5) A composition for stabilizing blood vessels, which contains a compound selected from the group consisting of the compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), and the compound represented by (IV). The compound (Kaempferol), and one or more components in the group formed by the salt.

(6) A composition for stabilizing lymphatic vessels, which contains a compound selected from the group consisting of the compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), and the compound (IV) One or more components in the group consisting of the compound (Kaempferol) and these salts.

(7) The composition according to any one of (2) to (6), wherein the vascular permeability inhibitory effect, the maturation effect of blood vessels, the normalizing effect of blood vessels, the stabilizing effect of blood vessels, or the stabilization of lymphatic vessels The chemical effect is due to the activation of Tie2.

(8) The composition of any one of (1) to (7), which is a food composition.

(9) The composition of any one of (1) to (7), which is a beverage composition.

(10) A composition as in any one of (1) to (9), which is optionally selected from the functions exerted by activation of Tie2, the function exerted by the inhibition of vascular permeability, and the maturation of blood vessels One or more of the group consisting of functions performed by the normalization of blood vessels, functions performed by the stabilization of blood vessels, and functions performed by the stabilization of lymphatic vessels Functional representation.

(11) The composition according to (10), in which the function expression is selected from "inhibition of hyperpermeability of blood vessels", "inhibition of intravascular factors from leaking out of blood vessels", "improving blood vessels to a normal state", and "reducing the Maintaining blood vessels in a normal state", "inhibiting the alienation of vascular endothelial cells", "inhibiting cell death of vascular endothelial cells", and "maintaining the function of rapid recovery of interstitial fluid" in one or more of the group consisting of.

(12) A use for activating Tie2 selected from the compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), and the compound represented by (IV) Use of one or more compounds (Kaempferol) and the group consisting of these salts.

(13) A method for activating Tie2, which is selected from the compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), and the compound represented by (IV) (Kaempferol) and one or more of the group consisting of these salts are used as active ingredients.

(14) A compound represented by the following formula (I),

(15) A compound represented by the following formula (II),

(16) A composition containing a compound such as (14) or (15).

(17) A composition containing compounds such as (14) and (15).

(18) The composition of (16) or (17), which is a food composition.

(19) The composition of (16) or (17), which is a beverage composition.

According to the present invention, it contains one or more components selected from the group consisting of novel iridoid glycoside compounds (Compound A and Compound B), oleanolic acid glycoside A, kaempferol, and their salts As a composition of active ingredients, it can exert Tie2 activation, vascular permeability inhibition, vascular maturation, vascular normalization, vascular stabilization, and lymphatic stabilization. In addition, by using the present invention to normalize blood vessels, the connection between vascular endothelial cells becomes stronger, and nutrients are transported to the skin through the blood vessels, thereby improving the elasticity or smoothness of the skin, preventing wrinkles and other cosmetic effects. In addition, by plugging the gaps between the endothelial cells of blood vessels or lymphatic vessels, improving blood flow and recovering water or excrement from tissues, it also obtains the effect of improving various symptoms such as cold sensitivity, stiff neck, edema, dark circles, etc. Or preventive effect.

[Figure 1] Figure 1 shows the chemical structures of novel iridoid glycoside compounds (Compound A and Compound B), oleanolic acid glycoside A, and kaempferol.

[Figure 2] Figure 2 shows the purification process of olive fruit extract.

^{[Figure 3] Figure 3 shows the 1} H-NMR and ¹³ C-NMR signals (Signal) of the novel iridoid glycoside compound (Compound A) and (Megaritolactonol).

[Figure 4] Figure 4 shows the results of the secondary NMR analysis of the novel iridoid glycoside compound (Compound A). Specifically, correlation-based displacement represents a spectral analysis, performed ¹ H- ¹ H correlation of the secondary element displacement ^{NMR (1 H- 1 H correlation spectroscopy} (COSY)) analysis and long-range ¹ H- ¹³ C correlation displacement of the second element NMR ( ¹ H-detected heteronuclear multiple bond connectivity (HMBC)) analysis result.

^{[Figure 5] Figure 5 shows the 1} H-NMR and ¹³ C-NMR signals of the novel iridoid glycoside compound (Compound B) and oleanoside A (Oleanoside A).

[Figure 6] Figure 6 shows the results of the secondary NMR analysis of the novel iridoid glycoside compound (Compound B). Specifically, it shows the results of ¹ H- ¹³ C long-distance displacement-related secondary NMR ( ¹ H-detected heteronuclear multiple bond connectivity (HMBC)) analysis as displacement-related spectral analysis.

[Figure 7] Figure 7 shows the Tie2 activation effect of novel iridoid glycosides (Compound A and Compound B), oleanolic acid A, kaempferol, hydroxytyrosol, and tyrosol and the control group ( DMSO) the result of the comparison.

[Figure 8] Figure 8 shows a novel iridoid glycoside compound (Compound A and Compound A and The result of the inhibitory effect of Compound B).

1. Composition 1-1. Composition

One aspect of the present invention is a composition containing one or more components selected from the group consisting of Compound A, Compound B, oleanolic acid A, kaempferol, and these salts as active ingredients Things.

The active ingredients contained in the composition of the present invention are compounds represented by the following formulas (I) to (IV).

The compounds represented by the aforementioned formulas (I) and (II) are novel iridoid glycoside compounds. The compound of the aforementioned formula (I) is represented by the IUPAC name as 2-(3,4-dihydroxyphenyl)ethyl (E)-2-(5-ethylene-2-oxotetrahydropyran-4- Yl)acetate (2-(3,4-dihydroxyphenyl)ethyl(E)-2-(5-ethylidene-2-oxotetrahydropyran-4-yl)acetate), which may be described as "Compound A" in this manual . In addition, the compound of the aforementioned formula (II) is represented by the IUPAC name as 2-(3,4-dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl )Acetic acid (2-(3,4- dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl)acetic acid) is described as "Compound B" in this manual. In addition, the compound represented by the aforementioned formula (III) is oleanoside A (Oleanoside A), and the compound represented by the aforementioned formula (IV) is kaempferol (Kaempferol).

The aforementioned compound in the present invention may be in the form of any salt (including inorganic salt and organic salt) that is pharmacologically acceptable. The term "salt" in this specification refers to any salt (including inorganic and organic salts) that is pharmacologically acceptable. For example, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, hydrochloride, Sulfate, nitrate, sulphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate, propionate, formate Acid salt, benzoate, picrate, benzenesulfonate, trifluoroacetate, etc.), but not limited to these. The salt of the compound of the present invention can be easily prepared by a person having ordinary knowledge in the field of the present invention by any method known in the field.

1-2. Isolation and synthesis of the active ingredients contained in the composition of the present invention

The active ingredients (Compound A, Compound B, oleanolic acid A, kaempferol, and/or these salts) contained in the composition of the present invention can be obtained by extracting and isolating natural substances, or by It is produced by a chemical synthesis method and is not particularly limited. When the active ingredient contained in the composition of the present invention is produced from a natural product, the natural product used as a raw material is not particularly limited, but, for example, olives are preferably used. Olive is a plant of Oleaceae. Although olive fruit can be used as the main raw material, it can also be mixed with leaves, seeds, Stems and so on. When olive fruits are used as a raw material, they can be used as they are raw, or dried by freeze drying or the like. In addition, the residue after squeezing the oil from the olive fruit can also be used directly or in a dried state. Preferably, the aqueous layer obtained by separating the liquid phase obtained from the olive fruit into an oil layer and an aqueous layer is to use only olive juice as a raw material.

Also, although the olive species is not particularly limited, for example, Manzanilo, Lucca, Nevadillo can be suitably used. Varieties of Branco, Mission, Picual, Arbequina, Hojiblanca, Cornicabra, Gordal, Moraiolo, Frantoio, Coratina, Leccino, etc.

Here, the so-called "olive juice" in the present invention refers to the extract obtained by separating the liquid phase obtained from the olive fruit extract into the oil layer and the water layer. Olive fruit extracts can also be extracted from olives using aqueous solvents, for example. Examples of the aqueous solvent include water and alcohols (for example, ethanol). Olive fruit extract can be directly used olive juice or aqueous solvent extract, or after filtering these, the polyphenols are concentrated in a suction column and spray-dried to obtain the extract.

Olive fruit extract can be obtained through the steps of separation and purification of olive fruit. In the olive fruit separation step, the olive fruit of the pressing raw material can be separated into oil and fruit juice by centrifugal separation to obtain olive juice. The pressing and centrifugal separation can be performed by a method well known to those having ordinary knowledge in the field of the present invention. In the purification step, the extract obtained by filtering and concentrating the olive juice obtained in the separation step can be used as the olive fruit extract in the present invention. In addition, the filtrate obtained by filtering the olive juice is added to the column filled with adsorbing resin. Sugars, minerals, and organic acids are equal to the adsorbing tree. After removing non-absorbent components from the fat, an aqueous solvent (such as water, ethanol, or a mixture of these) is used, and the eluted liquid can be used as an olive fruit extract. The type of sorption resin or the dissolution solvent of the column can be adapted to the type and form of olives used, and those skilled in the art of the present invention can appropriately set the conditions.

Although the extraction of the active ingredients contained in the composition of the present invention derived from raw materials derived from natural products can be carried out using a solvent, it is not limited thereto. As long as the active ingredient contained in the composition of the present invention can be extracted, any solvent can be used, and aqueous solutions such as water, buffer solutions, organic solvents, or combinations thereof can be used. The organic solvent may be used by general users, and for example, alcohols or ketones can be used. Examples of alcohols include lower alcohols (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, etc.), and liquid polyols (1,3-butenol, propylene glycol, glycerin, etc.) . Preferably, water-containing lower alcohols or lower alcohols are used. Examples of ketones include acetone and methyl ethyl ketone. Although the amount of solvent used can be appropriately set according to the amount of the raw material to be processed and the content of the target compound in the raw material, for example, 1.0~1000mL can be used relative to 1g of the raw material, preferably 2.0~500mL, and more preferably 5.0~100mL Solvent.

The effective ingredients contained in the composition of the present invention are extracted from the raw materials and can be further purified if necessary to increase the purity. Purification can be carried out by any method, for example, it can be carried out by chromatography. As chromatography, ion exchange chromatography, hydrophobic chromatography, hydrophilic chromatography, gel filtration chromatography, etc. are exemplified, but it is not limited to these. Moreover, although the purity of the standard product can be confirmed by LC-MS combining high-speed liquid chromatography, or high-speed liquid chromatography and mass analyzer, Not limited to this. Furthermore, the chemical structure of the active ingredient contained in the composition of the present invention can be analyzed by nuclear magnetic resonance (NMR) or mass spectrometry. Furthermore, the composition of the present invention does not contain any natural animals and plants that have not been processed at all.

In the case of chemically synthesizing the active ingredient contained in the composition of the present invention, the compound of the present invention can be produced by appropriately selecting the commonly known organic chemistry method using the available compound as a starting material.

1-3. Tie2 activation composition, etc.

One aspect of the present invention is a Tie2 activity containing at least one component selected from the group consisting of Compound A, Compound B, oleanolic acid A, kaempferol, and these salts as an active ingredient Chemical composition.

In the present invention, the "composition for Tie2 activation" refers to a composition having the ability to transform the active substance (phosphorylated Tie2) by phosphorylation of Tie2. In the stabilization of the capillary structure, the activation of a receptor called Tie2 that exists in vascular endothelial cells plays an important role. This Tie2 shows that in addition to vascular endothelial cells, it is also present in lymphatic endothelial cells. It is activated by angiogenin-1 released from parietal cells and strengthens the adhesion of skin cells to each other or parietal cells, which helps blood vessels. Stabilization of the structure. The activity of this Tie2, for example, has been reported to decrease with age, and it is very clear that this blood vessel or lymphatic vessel also ages. Accordingly, the Tie2 activating composition of the present invention can prevent and improve the aging of blood vessels or lymphatic vessels through the activating effect of Tie2.

Also, when the vascular structure becomes unstable due to the aging of the blood vessels, it comes from Nutrient components such as blood plasma components leak out, making it impossible to transport the necessary components to the necessary locations. As a result, it is considered that various troubles such as a decrease in skin condition are caused. Accordingly, in the Tie2 activation composition of the present invention, the vascular endothelial cells can be stabilized by the Tie2 activation effect, and the blood vessel permeation inhibitory effect can be exerted. Moreover, the endothelial cells of the blood vessels are firmly connected to obtain the cosmetic effects of transporting nutrients to the skin, improving the elasticity or smoothness of the skin, and preventing wrinkles. Furthermore, by plugging the gaps between the endothelial cells of blood vessels or lymphatic vessels, improving blood flow, recovering water or excrement from tissues, improving sensitivity to cold, stiff neck, edema, dark circles and other symptoms are prevented. effect. Accordingly, the present invention contains Tie2 activation with one or more components selected from the group consisting of Compound A, Compound B, oleanolic acid A, kaempferol, and these salts as an active ingredient The composition used may be the aforementioned composition having vascular permeability inhibition, vascular maturation, vascular normalization, vascular stabilization, or lymphatic stabilization.

As another aspect of the present invention, a composition for inhibiting vascular permeability, a composition for maturation of blood vessels, a composition for normalizing blood vessels, a composition for stabilizing blood vessels, a composition for stabilizing lymphatic vessels, etc. . These compositions preferably contain one or more components selected from the group consisting of Compound A, Compound B, oleanolic acid A, kaempferol, and these salts as an active ingredient.

In the present invention, "inhibition of vascular permeability" refers to suppression of the increase in vascular permeability caused by VEGF (vascular endothelial growth factor) or the like. The so-called "vascular maturation" refers to the induction of vascular endothelial cells and blood The adhesion of the vascular wall cells forms a plaque between the vascular endothelial cells that the environmental factors in the blood vessel cannot easily leak to the outside of the blood vessel. The so-called "normalization of blood vessels" refers to improving the adhesion of vascular endothelial cells to each other, and by promoting the lining of vascular endothelial cells to vascular wall cells, abnormalities such as blood vessels with failure of vascular permeability or disordered proliferation of blood vessels will be induced The blood vessels return to their normal state. The so-called "stabilization of blood vessels" refers to the effect of inhibiting the damage to existing blood vessels, the alienation of vascular endothelial cells, the alienation of vascular endothelial cells and vascular wall cells, and the inhibition of cell death of vascular endothelial cells. The so-called "lymphatic vessel stabilization" refers to the proper arrangement of lymphatic endothelial cells to stabilize the lymphatic vessels by forming a lining and maintain the function of rapid recovery of interstitial fluid.

1-4. The content of active ingredients in the composition

The contents of Compound A, Compound B, oleanolic acid A, kaempferol, and these salts in the composition of the present invention, considering the dosage form, method of administration, etc., if the desired effect of the present invention is obtained A general amount is sufficient, and it is not specifically limited. For example, in the case of using Compound A as the active ingredient, the content of Compound A in the composition of the present invention relative to the total amount of the composition is 0.01% to 99% by weight, preferably 0.1% to 50% by weight, It is more preferably 1% by weight to 30% by weight, and still more preferably 10% by weight to 30% by weight. When Compound B is used as an active ingredient, the content of Compound B in the composition of the present invention relative to the total amount of the composition is 0.01% to 99% by weight, preferably 0.1% to 50% by weight, more preferably 1% by weight to 30% by weight, more preferably 10% by weight to 30% by weight. In the case of using oleanolic acid glycoside A as the active ingredient, the content of oleanolic acid glycoside A in the composition of the present invention relative to the total amount of the composition is 0.01% to 99% by weight, preferably 0.1% by weight %~50% by weight, more preferably 1% by weight to 30% by weight, still more preferably 10% by weight to 30% by weight. When kaempferol is used as an active ingredient, the content of kaempferol in the composition of the present invention is 0.001% to 99% by weight, preferably 0.01% to 50% by weight, more preferably, relative to the total amount of the composition. It is 0.1% by weight to 30% by weight, and more preferably 1% by weight to 30% by weight. Unless otherwise specified, the "weight%" used in this specification means weight/weight (w/w)% by weight. In addition, when the various active ingredients are in the form of salts, hydrates, etc., the above-mentioned content is calculated by converting this into a free body (free body).

The content of Compound A, Compound B, oleanolic acid A, kaempferol, and their salts can be determined according to methods well known to those with ordinary knowledge in the field of the present invention. For example, by using LC-MS/MS, HPLC, etc., appropriate conditions can be set in accordance with the types of active ingredients, etc., for measurement.

1-5. Other ingredients

The composition of the present invention may contain any additives or ingredients in addition to the active ingredients according to its form. Although these additives and/or components are not particularly limited, for example, excipients, binders, disintegrants, lubricants, antioxidants, preservatives, flavoring agents, flavoring agents, coloring agents, perfumes, etc. can be used The additives. For example, L-ascorbic acid, catechins, dextrin, cyclodextrin, calcium carbonate, trehalose, etc. can be used. Also, the composition may contain well-known The ingredients may also contain well-known ingredients that are effective in preventing aging of blood vessels or beautifying. For example, saponaria, yellow berry, ginkgo, oyster, turmeric, chrysanthemum, jujube, wolfberry, chamomile, false leaf tree, hawthorn, carambola, bright mountain ginger, lotus root, South African tea, tamarind can be used to report the activation of Tie2 , Hawthorn, guava leaf, tuber, Siberian ginseng, mango ginger, ginseng, milk seed, wingless salsola, thornwood, loosestrife, serval, big wild yam, three leaf empty wood, Haizhou Changshan Extracts of wild papaya, small red car, scutellaria, sawtooth oak, gooseberry, crystal persimmon, plantain, scallion white, bayberry, cinnamon, scallion thorn, polygonatum, polygonatum odoratum, melon, Morinda officinalis Vascular endothelium is effective in improving grape seed or pine bark, peanut seed coat, lychee seed coat extracts containing proanthocyanidins, or amino acids such as L-citrulline and L-arginine.

1-6. Purpose

The composition of the present invention can exhibit various physiological effects as described above. For example, by applying the composition of the present invention, the vascular permeability inhibitory effect, the maturation effect of blood vessels, the normalizing effect of blood vessels, the stabilizing effect of blood vessels, the stabilizing effect of lymphatic vessels, the activating effect of Tie2, etc. can be exerted, thereby It can also improve skin elasticity and smoothness, prevent wrinkles and other cosmetic effects, and improve and prevent sensitive cold, stiff neck, edema, and dark circles.

The composition of the present invention can also be applied to either therapeutic use (medical use) or non-therapeutic use (non-medical use). Examples of the composition include pharmaceuticals (medical compositions), foods and beverages (including food, beverages, food and beverage compositions, food compositions, and beverage compositions), and cosmetics. (Cosmetic composition) etc., but it is not limited to these.

The composition of the present invention can be formulated into solid forms such as tablets (including coated tablets), granules, powders, powders, or capsules, or oral liquids, suspensions, etc., by well-known methods. , Emulsions, slurries, or liquids such as drinks. These agents can be taken directly or with water. In addition, after being prepared into a form that can be easily blended (for example, powder form or granular form), for example, it can be used as a raw material for pharmaceuticals or food and beverages, but it is not limited to this form.

The composition of the present invention can be arbitrarily selected as the dosage form of cosmetics (cosmetic composition) according to the purpose. For example, it can be a dosage form of cream, ointment, lotion, solution, gel, powder, granule, etc. The form of lotion, powder and stick. The preparation form can also be an aqueous solution, solubilization, emulsification, powder, oil, gel, ointment, aerosol, water-oil two-layer system, and water-oil-powder three-layer system A wide range of patterns. That is, if it is a basic cosmetic, it can be widely used in facial cleansers, lotions, lotions, lotions, creams, gels, essences (beauty liquids), packs, masks, massage agents, foundations, lipsticks, bathing agents, Shampoo, conditioner, hair conditioner, ointment, cream, and sheet products (absorbent articles such as sanitary products, wipes, wet tissues, etc.), etc. Moreover, it is not limited to the dosage form and form of this invention. In addition, by using these dosage forms, various oils, surfactants, gelling agents, preservatives, antioxidants, solvents, alcohols, water, chelating agents, thickeners, ultraviolet absorbers, emulsifiers can be appropriately blended Stabilizers, pH adjusters, colors and fragrances, etc.

As specific examples of the beverage of the present invention, oolong tea beverages, red Tea drinks, green tea drinks, fruit juice drinks, vegetable juices, sports drinks, isotonic drinks, fortified water, mineral water, Near water, nutritional drinks, beauty drinks, or various alcoholic drinks, etc.

In addition, if the beverage of the present invention needs to go through steps such as sterilization, it becomes a canned beverage in a container. For example, it is possible to produce a sterilized canned beverage in a container by a method such as heat sterilization after filling the beverage in a container, or a method of filling the container in an aseptic environment after the beverage is sterilized.

The types of containers used for canned beverages are not particularly limited. For example, resin containers such as plastic bottles, paper containers such as paper bags, glass containers such as glass bottles, and metal containers such as aluminum cans or steel cans. , Aluminum bags, etc., can be used in containers commonly used for beverages.

Although the food and beverages of the present invention are not particularly limited, for example, health foods, functional foods (including specific health foods, conditional specific health foods, nutritional functional foods, and functional foods), special purpose foods, or Health supplements, etc. The content of the aforementioned active ingredients in the food and drink of the present invention is as described above for the composition system.

The food and drink of the present invention, for example, when preparing a well-known food and drink, the aforementioned active ingredients are mixed with a predetermined amount of the raw material and can be prepared in accordance with a known method for producing food and drink. The effective ingredient is added and prepared in such a way that it becomes the aforementioned predetermined amount. Still, well-known foods and beverages may originally contain the aforementioned effective ingredients, and if the aforementioned effective ingredients become the aforementioned predetermined amount, they can be appropriately blended and prepared.

The composition of the present invention can be applied with an appropriate method according to the form. If the applicable method is that the active ingredients of the present invention can migrate into the circulating blood, then It is not particularly limited. For example, it can be in the form of solid preparations for oral use, liquid preparations for oral use such as oral liquid preparations or slurries, or parenteral preparations such as injections, external preparations, suppositories, or transdermal absorption preparations, but not Was limited to this. However, the term "applicable" in this manual refers to all aspects including ingestion, ingestion, drinking, and transdermal absorption.

The applicable amount of the composition of the present invention is set at a proper time depending on its form, administration method, purpose of use, and age, weight, and symptoms of the patient or diseased animal to be administered, and it is not always certain. The effective human intake of the composition of the present invention is also not constant and is not particularly limited. The effective human intake of the composition of the present invention is, for example, 0.1 mg to 400 mg (0.002 mg/kg to 8 mg/kg) per day for a person weighing 50 kg, preferably 1 mg to 300 mg (0.02 mg/kg to 6 mg/ kg), more preferably 10mg~200mg (0.2mg/kg~4mg/kg). Still, the application of the composition of the present invention is within the expected intake range, and can be divided into single or several times within one day. The applicable period is also arbitrary. The effective human intake of the composition of the present invention refers to the intake of the composition of the present invention showing effective effects in humans, and the types of active ingredients contained in the composition are not particularly limited.

The applicable objects of the composition of the present invention are preferably humans, but can also be domestic animals such as cattle, horses, goats, pet animals such as dogs, cats, rabbits, or, mice, rats, guinea pigs, and monkeys. And other experimental animals. In the case of applying animals other than humans as the target, the daily application amount per mouse (approximately 20g) is determined by the content of the active ingredient in the composition, the status of the target person, weight, gender, and age, etc. The conditions vary, but for example, 0.002mg/kg~8mg/kg, preferably 0.02mg/kg~6mg/kg, more preferably It is 0.2mg/kg~4mg/kg.

In another aspect, the present invention relates to the expression of the functions exerted by the inhibition of vascular permeability, the maturation of blood vessels, the normalization of blood vessels, the stabilization of blood vessels, the stabilization of lymphatic vessels, or the activation of Tie2. The composition of the agent of the present invention. Such expressions or functional expressions are not particularly limited, but examples include "inhibition of hyperpermeability of blood vessels", "inhibition of intravascular factors from leaking out of blood vessels", "improving blood vessels to a normal state", and "maintaining blood vessels". In a normal state", "inhibit the alienation of vascular endothelial cells", "inhibit the cell death of vascular endothelial cells", or "maintain the function of rapid recovery of interstitial fluid", etc., or can be equated with these. Functional representation. In this specification, the expressions such as the expressions and functional expressions can be attached to the composition itself, or to the container or packaging of the composition.

2. To activate the use of Tie2

One aspect of the present invention is one or more selected from the group consisting of Compound A, Compound B, oleanolic acid A, kaempferol, and these salts for inhibiting vascular permeability, vascular The use of maturation, normalization of blood vessels, stabilization of blood vessels, stabilization of lymphatic vessels, or activation of Tie2 is preferably used for activation of Tie2.

Furthermore, by activating Tie2 by the use of the present invention, vascular permeability inhibitory effects, vascular maturation effects, vascular normalization effects, vascular stabilization effects, and lymphatic stabilization effects can also be obtained. The use is for human or non-human animal use. It can be used for treatment or non-treatment usage of. Here, the so-called "non-therapeutic" refers to medical behavior, which does not include the concept of treatment of the human body through treatment.

3. How to activate Tie2

One aspect of the present invention is a Tie2 activation method, which will be selected from at least one selected from the group consisting of Compound A, Compound B, oleanolic acid A, kaempferol, and these salts Use as an active ingredient. Specifically, one aspect of the present invention provides a method for activating Tie2, which includes activating Tie2 as a necessary object and administering a therapeutically effective amount of the aforementioned active ingredients. In addition, the so-called Tie2 activation is a necessary object, and the composition system is as described above.

In addition, one aspect of the present invention is also a method, which is selected from at least one selected from the group consisting of Compound A, Compound B, oleanolic acid A, kaempferol, and these salts It is used as an active ingredient to inhibit vascular permeability, mature blood vessels, normalize blood vessels, stabilize blood vessels, or stabilize lymphatic vessels.

In addition, the therapeutically effective dose in this specification means that one or more selected from the group consisting of Compound A, Compound B, oleanolic acid A, kaempferol, and these salts are ingested by the subject. In this case, the amount of Tie2 activated is obtained by comparing it with a non-ingested subject. As a specific effective amount, it is not always certain that it may be set at a proper time depending on the form of administration, the method of administration, the purpose of use, and the age, weight, symptoms, etc. of the subject.

In the method of the present invention, in order to become the aforementioned therapeutically effective amount, the aforementioned effective ingredient can be used directly or as a composition containing the aforementioned effective ingredient Dosing.

4. Novel iridoid glycoside compounds

One aspect of the present invention is a novel iridoid glycoside compound represented by the following formula (I) or (II).

Still, the compound of the aforementioned formula (I) is represented by the IUPAC name as 2-(3,4-dihydroxyphenyl)ethyl (E)-2-(5-ethylene-2-oxotetrahydropyridine) Pyran-4-yl)acetate (2-(3,4-dihydroxyphenyl)ethyl(E)-2-(5-ethylidene-2-oxotetrahydropyran-4-yl)acetate), in this specification, it is described as " Compound A". In addition, the compound of the aforementioned formula (II) is represented by the IUPAC name as 2- (3,4-Dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl)acetic acid (2-(3,4-dihydro-3-hydroxymethyl- 5-methoxycarbonyl-2-methyl-2H-pyran-4-yl)acetic acid) is described as "Compound B" in this manual.

The compound of the present invention may be in the form of any salt (including inorganic salt and organic salt) that is pharmacologically acceptable. The term "salt" in this specification is the same as described above. If it is any salt (including inorganic salt and organic salt) that is pharmacologically acceptable, it is not particularly limited. Examples include sodium salt, potassium salt, calcium salt, and magnesium salt. , Ammonium salt, hydrochloride, sulfate, nitrate, sulphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate Acid salt, propionate, formate, benzoate, picrate, benzenesulfonate, trifluoroacetate, etc.). The salt of the compound of the present invention can be easily prepared by a person having ordinary knowledge in the field of the present invention by any method known in the field.

4-1. Manufacturing method of novel iridoid glycoside compounds

The novel iridoid glycoside compounds (Compound A, Compound B) of the present invention can be prepared by extraction and isolation from natural products, or can be prepared by chemical synthesis methods, and are not particularly limited. When it is made from a natural product, although the natural product used as a raw material is not particularly limited, it is particularly preferable to use olives. Olive is a plant in the Oleaceae family. Although olive fruit can be used as the main raw material, it can also be mixed with leaves, seeds, stems, etc. When olive fruits are used as a raw material, they can be used as they are raw, or dried by freeze drying or the like. Also, the residue after squeezing the oil from the olive fruit is also It can be used directly or in a dried state. Preferably, the aqueous layer obtained by separating the liquid phase obtained from the olive fruit into an oil layer and an aqueous layer is to use only olive juice as a raw material. The composition of "olive" and "olive juice" is as described above.

The extraction of the novel iridoid glycoside compound of the present invention derived from raw materials derived from natural products (for example, olive fruit extract, etc.) can be carried out using a solvent, but is not limited thereto. As long as the active ingredient contained in the composition of the present invention can be extracted, any solvent can be used, and aqueous solutions such as water, buffer solutions, organic solvents, or combinations thereof can be used. The organic solvent may be used by general users, and for example, alcohols or ketones can be used. Examples of alcohols include lower alcohols (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, etc.), and liquid polyols (1,3-butenol, propylene glycol, glycerin, etc.) . Preferably, water-containing lower alcohols or lower alcohols are used. Although the amount of solvent used can be appropriately set according to the amount of the raw material to be processed and the content of the target compound in the raw material, for example, 1.0~1000mL can be used relative to 1g of the raw material, preferably 2.0~500mL, and more preferably 5.0~100mL Solvent.

After the novel iridoid glycoside compound of the present invention is extracted from the raw material, it can be further purified to improve purity if necessary. Purification can be carried out by any method, for example, it can be carried out by chromatography. As chromatography, ion exchange chromatography, hydrophobic chromatography, hydrophilic chromatography, gel filtration chromatography, etc. are exemplified, but it is not limited to these. Moreover, although the purity of the standard product can be confirmed by combining high-speed liquid chromatography or LC-MS with a mass analyzer, it is not limited to this. Furthermore, the chemical structure of the novel iridoid glycoside compound of the present invention can be analyzed by nuclear magnetic resonance (NMR) or mass spectrometry.

In the case of chemically synthesizing the novel iridoid glycoside compound of the present invention, the available compound is used as a starting material, and the desired compound can be produced by appropriately selecting a commonly known method of organic chemistry.

4-2. Composition

One aspect of the present invention is a composition containing Compound A and/or Compound B. As mentioned above, Compound A and Compound B of the novel iridoid glycoside compounds of the present invention have a variety of physiological effects, such as Tie2 activation, vascular permeability inhibition, vascular maturation, and vascularization. Normalization, vascular stabilization, and lymphatic stabilization, etc. Accordingly, the aforementioned composition of the present invention has a Tie2 activation effect, a vascular permeability inhibitory effect, a blood vessel maturation effect, a blood vessel normalization effect, a blood vessel stabilization effect, or a lymphatic vessel stabilization effect in a certain aspect. Actors. In addition, the aspect of the composition may include pharmaceuticals (medical composition), food and beverage (including food, beverage, food composition, food composition, and beverage composition), cosmetics (cosmetic composition), etc. It is not limited to these.

The Compound A and/or Compound B contained in the composition of the present invention can be obtained by extraction and isolation from natural materials as described above, or can be obtained by a chemical synthesis method, and is not particularly limited. When the active ingredient contained in the composition of the present invention is prepared from natural products, the natural products used as raw materials are not particularly limited, but olives are preferably used. In addition, the single ionization and synthesis method of Compound A and/or Compound B is also the same as described above. Still, the composition of the present invention does not include natural plant and animal origin Those who have not been processed at all, or the extract itself is not blended with other ingredients.

Although the content of Compound A and/or Compound B in the composition of the present invention is not particularly limited, for example, the content of Compound A in the composition of the present invention is 0.01% by weight to 99% by weight relative to the total amount of the composition. , Preferably 0.1% by weight to 50% by weight, more preferably 1% by weight to 30% by weight, still more preferably 10% by weight to 30% by weight. The content of Compound B in the composition of the present invention is relative to the composition The total amount of the substance is 0.01% by weight to 99% by weight, preferably 0.1% by weight to 50% by weight, more preferably 1% by weight to 30% by weight, and still more preferably 10% by weight to 30% by weight. Still, other ingredients that can be blended into the composition are as described above.

[Example]

Hereinafter, the present invention will be described in more detail based on examples. However, the present invention is not limited to these embodiments.

Example 1: Structural determination of Compound A and Compound B 1-1. Preparation of olive fruit extract

The olive fruits are squeezed and centrifuged to separate them into oil and juice. After filtering the olive juice obtained here, in the column of the absorption system, remove the non-absorbent components from sugars, minerals, and organic acids equal to the absorption resin, and concentrate the water-alcohol dissolving part to make it spray-dried as olive fruit The extract is used. Next, the fruit extract (500g) was subjected to column chromatography using Dia ion HP20 (resin volume; 10L, dissolution solvent; ethanol: water (0: 100→70:30)), the olive fruit extract was fractionated to obtain the following fractions (Fr.1: 179g, Fr.2: 120g, Fr.3: 85g, Fr.4: 71g, Fr.5: 26g ). Fr.4 (50% ethanol elution part, 20g) is subjected to column chromatography using Toyopearl HW-40C (resin volume; 500mL, dissolution solvent; methanol: Water (10:90→70:30)→acetone:water (70:30)), Fr.4 was fractionated into 19 fractions (Fr.4a~Fr.4s). For the fraction Fr.4k with Tie2 activity recognized by Fr.4a~Fr.4s, HPLC (Preparative HPLC) was performed under the following analysis condition 1, and then divided into 6 fractions (Fr.4ka~4kf). In the fraction with the highest Tie2 activity recognized by Fr.4ka~Fr.4kf, Fr.4kb and Fr.4kd were purified using the following analysis condition 2 and analysis condition 3 using Preparative HPLC (Preparative HPLC), isolated from Compound A (46.2mg), Compound B (19.5mg) and Oleanoside A (98.1mg). Still, for Fr.4r, which was determined to have Tie2 activity, HPLC (Preparative HPLC) was also performed under analysis condition 4, and Kaempferol (3.7 mg) was isolated. In addition, Fig. 2 shows the purification process of olive fruit extract.

<Analysis Condition 1>

Detection: 220nm

Flow rate: 15mL/min

3.0×25.0cm(SHISEIDO) Column: Capcell Pack C18 TYPE AQ

3.0×25.0cm(SHISEIDO)

Mobile phase: CH ₃ CN: H ₂ O (32: 68)

Column temperature: room temperature 25℃

<Analysis Condition 2>

Detection: 220nm

Flow rate: 10mL/min

2.15×30.0cm(TOSOH) Column: TSK-Gel Amide-80

2.15×30.0cm(TOSOH)

Mobile phase: CH ₃ CN: H ₂ O (0min, 100:0→15min, 100:0→20min, 80:20→35min, 80:20)

Column temperature: room temperature 25℃

<Analysis Condition 3>

Detection: 220nm

Flow rate: 10mL/min

2.0×25.0cm(nacalai tesque) Column: COSMOSIL Cholester

2.0×25.0cm(nacalai tesque)

Mobile phase: CH ₃ CN: H ₂ O (20:80)

Column temperature: room temperature 25℃

<Analysis Condition 4>

Detection: 280nm

Flow rate: 15mL/min

3.0×25.0cm(SHISEIDO) Column: Capcell Pack C18 TYPE AQ

3.0×25.0cm(SHISEIDO)

Mobile phase: CH ₃ CN: H ₂ O (27: 73)

Column temperature: room temperature 25℃

1-2. Structure analysis of Compound A

It is understood that Compound A is obtained as a colorless oily substance. As a result of high-resolution electrospray-ionization mass spectrometry (HRESI-MS), it has the molecular formula C ₁₇ H ₂₀ O ₆ . In addition, from the UV spectrum pattern (λmax 282), it is estimated that this compound has a benzene ring in the molecule. Secondly, in ¹ H-nuclear magnetic resonance ( ¹ H-NMR), by observing the ABX system signal (Signal) as 1 group (δ _H : 6.62 (1H, dd, J=2.0, 8.0 Hz), 6.74 (1H) ,d,J=2.0Hz), 6.82 (1H,d,J=8.0Hz)], and ^{8 peak patterns observed in 13} C-NMR (δ _c : 34.6, 66.0, 115.5, 116.4, 121.3, 130.7, 143.5, 143.6), disclosing the presence of hydroxytyrosol. Furthermore, in ¹ H-NMR, it was confirmed that there were 1 signal derived from methyl groups, 3 signals derived from methylene groups, 1 signal derived from methine groups, and 1 olefin proton. In ¹³ C-NMR, when confirming for units other than hydroxytyrosol, it was confirmed that there were 1 signal derived from methyl group, 3 signals derived from methylene group, and 2 signals derived from methine group. There are 3 signals from grade 4 carbon. Then, for the purpose of clarifying these binding patterns, ¹ H- ¹ H correlation spectroscopy ( ¹ H- ¹ H COSY), ¹ H-detected multiple quantum coherence (HMQC), ¹ H-detected multiple-bond connectivity (HMBC ), when analyzing these in detail, it is understood that the structure of this unit is a compound characterized by iridoid glycosides. With reference to the report example of the isolation of iridoid glycosides derived from olives, through detailed analysis of the spectral data centered on the 2D NMR, it is revealed that the iridoid glycoside unit of the current structure is clearly the 3rd position of Megaitolactonol The hydroxy group is transformed into a carboxyl group.

Next, when analyzing the HMBC used to study the binding pattern of each unit, it was confirmed that the proton at the 8'position of the hydroxytyrosol unit is related to the carbonyl carbon at the 3 position of Megaitolactonol, so it was found that the two units are the 8'of hydroxytyrosol. The position and the 3 position of Megaitolactonol are ester bonds. From the above spectral data, determine the structure of Compound A. ^{The 1} H-NMR and ¹³ C-NMR signals of Compound A and Megaitolactonol are shown in FIG. 3. In addition, ^{the results of the 2D NMR analysis (1} H- ¹ H correlation spectroscopy (COSY) analysis and ¹ H-detected heteronuclear multiple bond connectivity (HMBC) analysis) of Compound A are shown in FIG. 4.

1-3. Structure analysis of Compound B

Compound B is obtained as a colorless oily substance. In ¹ H-NMR, it is confirmed that there are 1 signal derived from methyl group, 2 groups of signal derived from methylene group, 3 signals derived from methine group, and 1 signal derived from methoxy group. The number of signals derived from olefins is one. In ¹³ C-NMR, it can be confirmed that there are 2 methyl groups (δ _c : 19.4, 51.5), 2 methylene groups (δ _c : 38.2, 62.3), and 4 methine groups (δ _c : 29.6, 45.0) , 74.1, 156.2), there are 3 grade 4 carbons (δ _c : 108.5, 169.3, 174.3), a total of 11 carbon signals. ^{Since the above 1} H-NMR and ¹³ C-NMR results and UV absorption cannot be confirmed, it is speculated that this compound is an iridoid glycoside. Next, for the purpose of confirming these binding patterns, analysis of ^{2D NMR (1} H- ¹ H COSY, HMQC, HMBC) reveals the structure of this compound. The structure clear from the above analysis is similar to that of Oleanoside reported as one of the components of olive fruit. When comparing these spectral data, it can be confirmed that the 6-digit, 7-digit, and 8-digit signals are removed. Good connection.

In addition to the above results, in this compound, the structure of Compound B was determined based on the results of the HMBC correlation to the carbonyl carbon at the 7th position and the molecular weight obtained from MS based on the methylene at the 8th position. ^{The 1} H-NMR and ¹³ C-NMR signals of Compound B and oleanolic acid A are shown in FIG. 5. In addition, the results of the 2D NMR analysis of Compound B ( ¹ H- ¹ H correlation spectroscopy (COSY) analysis and ¹ H detected heteronuclear multiple bond connectivity (HMBC) analysis) are shown in FIG. 6. Still, Oleanoside A and Keampferol were identified by comparison with the literature value recorded in the paper.

Example 2: Evaluation of Tie2 activation

Compound A and Compound B were dissolved in serum vascular endothelial cell proliferation medium (manufactured by Kurabo Industries Co., Ltd., Humedia-EG2) so that the final concentration became 10 μg/mL to prepare test samples. In addition, the test sample dissolved in Humedia-EG2 was prepared so that Angiogrowin-1 had a concentration of 500 ng/mL, and used as a positive control group.

Next, normal human umbilical vein endothelial cells (HUVEC) cultured until confluence ^{were seeded into 96 plugs so that they would become 2.0×10 4} cells/0.1 mL/acupoint, and cultured overnight with Humedia-EG2. The HUVECs cultured overnight were replaced with 0.1 mL of vascular endothelial cell basal medium (manufactured by Kurabo Industries Co., Ltd., Humedia-EB2) 3 hours before cell stimulation (addition of test material), and re-cultured. Then, add 0.1 mL of the test sample to the acupuncture point and incubate for 20 minutes. After culturing, an immunoassay kit (manufactured by R&D Systems, Human Phospho-Tie2 (Y992) Immunoassay) was used to measure the amount of phosphorylated Tie2 in the cells in accordance with the agreement. In addition, as a negative control group, the phosphorylated Tie2 was also measured for the dimethylsulfoxide (DMSO) used for the dissolution of the test sample. Furthermore, the Tie2 activation rate was calculated according to the following formula to evaluate the phosphorylation effect.

Tie2 activation rate (%) = the measured value of phosphorylated Tie2 when the test sample was added / the measured value of phosphorylated Tie2 in the negative control group) × 100

The results are shown in Table 1 and Fig. 7. As shown in Table 1 and Fig. 7, the activation of Tie2 was confirmed in Compound A, Compound B, oleanolic acid A, and kaempferol.

Example 3: Inhibition of vascular permeability of Compound A and Compound B

The DMSO solution (25μM) of Compound A or B prepared in Example 1 is used in the test sample, and it will be effective against the vascular permeability caused by the vascular endothelial growth factor (VEGF). The inhibitory effect of hyperplasia was evaluated by the Miles assay. This animal experiment complies with other related laws of the Animal Care and Management Act The order has been reviewed by the in-house animal experiment committee and implemented in accordance with the plan approved by the chief of the agency.

3-1. Test method

After 8-week-old Balb/c female mice were preliminarily reared for more than 1 week, 8 drug-administering compartments were set for each animal (clamping 4 on the left and right sides of the midline of the back), and n=6 was evaluated.

After 15 minutes of intravenous administration of 1% Evans blue pigment prepared in physiological saline under anesthesia, an equal amount of VEGF (final concentration 300ng/mL) and each test sample were mixed, and 15 μL was administered to the back skin Inside. After 40 minutes of intradermal administration, the pigment leaked from the skin was extracted with 500 μL of formamide, and the amount of pigment was quantified by absorbance at 620 nm. Moreover, a compartment where neither VEGF nor the tested sample is administered and a compartment where only VEGF is administered are also provided. Dunnett's multiple comparison test was used in the significant difference test.

3-2. Results

The amount of the leaked Evans Blue pigment is shown in FIG. 8. Based on the vascular permeability inhibition rate of the tested sample, Compound A is 89% and Compound B is 139%. From the above, it is confirmed that both Compound A and Compound B have the effect of inhibiting the permeability of blood vessels.

〔Industrial availability〕

The present invention provides Tie2 activation effects, vascular permeability inhibitory effects, vascular maturation effects, vascular normalization effects, and vascular safety Compositions for the stabilization effect and the stabilization effect of the lymphatic vessels, etc. In this way, the present invention provides a novel composition with better physiological activity, etc., which can be used in food and beverages and the like.

Claims (14)

A composition for Tie2 activation, which is composed of a compound selected from the group consisting of the compound represented by (I) below, the compound represented by (II) below, the compound (Oleanoside A) represented by (III) below, and their salts One or more ingredients in the group:

A composition for inhibiting vascular permeability, which contains at least one component selected from the group consisting of the compound represented by claim 1 and the salt thereof. A composition for maturation of blood vessels, which contains at least one component selected from the group consisting of the compound represented by claim 1 and the salt thereof. A composition for the normalization of blood vessels, which contains one or more components selected from the group consisting of the compound represented by claim 1 and the salt thereof. A composition for stabilizing blood vessels, which contains at least one component selected from the group consisting of the compound represented by claim 1 and the salt thereof. A composition for stabilizing lymphatic vessels, which contains at least one component selected from the group consisting of the compound represented in claim 1 and the salt thereof. Such as the composition of any one of Claims 2 to 6, wherein the inhibitory effect of vascular permeability, the maturation effect of blood vessels, the normalization effect of blood vessels, the stabilization effect of blood vessels, or the stabilization effect of lymphatic vessels are caused by Tie2 activation effect. For example, the composition of any one of claims 1 to 6, which is a food composition. For example, the composition of any one of claims 1 to 6, which is a beverage composition. Such as the composition of any one of Claims 1 to 6, which is optionally selected from the functions exerted by activation of Tie2, the functions exerted by the inhibition of vascular permeability, and the functions exerted by the maturation of blood vessels , The expression of more than one function in the group consisting of the function exerted by the normalization of blood vessels, the function exerted by the stabilization of blood vessels, and the function exerted by the stabilization of lymphatic vessels. Such as the composition of claim 10, in which the function expression is selected from "inhibition of hyperpermeability of blood vessel", "inhibition of leakage of intravascular factors out of the blood vessel", "improving the blood vessel to a normal state", and "maintaining the blood vessel in Normal state", "inhibit the alienation of vascular endothelial cells", "inhibit One or more of the group consisting of "cell death of vascular endothelial cells" and "maintaining the function of rapid recovery of interstitial fluid". A compound represented by the following formula (I),

A compound represented by the following formula (II),

A food and beverage composition containing the compound of claim 12 and/or 13.

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